WO1999006398A1

WO1999006398A1 - 1,3-oxazolinyl-biphenyl derivatives, preparation method and use as synthesis intermediates

Info

Publication number: WO1999006398A1
Application number: PCT/FR1998/001651
Authority: WO
Inventors: Bertrand Castro; Jean-Robert Dormoy; Mateusz Mach; Mieczyslaw Makosza; Jacek Pankowski
Original assignee: Sanofi-Synthelabo
Priority date: 1997-07-29
Filing date: 1998-07-27
Publication date: 1999-02-11
Also published as: FR2766821A1; AU8868498A

Abstract

The invention concerns 1,3-oxazolin-2-yl-1,1'biphenyl derivatives of general formula (I) in which R represents hydrogen or the methyl radical.

Description

"1,3-oxazolinyl-biphenyl derivatives, process for their preparation and their use as synthesis intermediates"

The present invention relates, in general, to new derivatives of oxazolin-2-yl-1, 1'-biphenyl, to their preparation process and to their use as synthesis intermediates. More specifically, the subject of the invention is the derivatives of 2- (1, 3-oxazolin-2-yl) - 4'-phthalimidomethyl-1, 1 '-biphenyl of general formula:

in which R represents hydrogen or methyl.

The compound of formula I in which R represents methyl can be regarded as a preferred compound.

The compounds of the invention have proved to be particularly useful as intermediate products, in particular for the preparation of 4'-aminomethyl-2-cyano-1, 1 '-biphenyl of formula:

The latter can itself be widely used as a synthesis intermediate, for example for the preparation of various pharmacologically active compounds. As such, there may be mentioned biphenyl derivatives angiotensin II receptor antagonists corresponding to the general formula:

in which Am represents a spirocyclopentane-ketoimidazolinyl, 1 H-imidazolyl or 1 H-benzimidazolyl group, this group itself comprising one or more substituents selected from halogen atoms, C _π -C ₄ alkyl groups, C1-C4 aikoxy and carboxylic.

The 2-n-butyl-4-spirocyclopentane-5-keto-2-imidazolin-1 -yle group of formula:

represents a preferred Am group.

The compounds of formula Ib, which can be used in the treatment of cardiovascular conditions, such as hypertension or heart failure, have been described in particular in US patents 5,138,069, 5,196,444 and 5,529,233.

Among the most interesting biphenyl derivatives of formula I b, there may be mentioned: 2-butyl-3- [p- {2- (1 H-tetrazol-5-yl) phenyl} benzyl] -1, 3-diazaspiro [4,4] non-1-en-4-one or irbesartan 2-ethoxy-1- [4- [2- (1 H-tetrazol-5-yl) phenyl] benzyl] 1 H- benzimidazole- 7-carboxylic or candesartan 2-butyl-4-chloro-1 - [[2 '- (1 H-tetrazol-5-yl) -1, 1' -biphenyl- 4yl] methyl] -1 H-imidazole-5 -methanol or losartan. Irbesartan however constitutes a preferred compound of formula I b. Most of the known processes for the preparation of biphenyl derivatives of formula I b or analogues of these derivatives involve the formation of a common intermediate, namely 4'-bromomethyl-2-cyano-1, 1'- biphenyl.

However, this bromine derivative has the major drawbacks of being a tear gas and an allergen therefore requiring handling precautions such as, for example, confinement or use in solution.

The search for a process allowing the preparation of biphenyl derivatives of formula I b, or analogues thereof, while not having the disadvantages reported above, therefore remains of undoubted interest.

Now, it has surprisingly been found, according to the invention, that the derivatives of 2- (1, 3-oxazolin-2-yl) -4'-phthalimidomethyl-1, 1 '-biphenyl of formula I make it possible to prepare the compounds of formula I b or analogues according to a method devoid of the drawbacks mentioned above in that it avoids the passage through 4'-bromomethyl-2-cyano-1, 1 '-biphenyl intermediate in favor of 4'-aminomethyl-2 -cyano-1, 1 '-biphenyle. This 4'-aminomethyl derivative, which can be advantageously prepared starting from the compounds of formula I since the yields obtained are of the order of 70% to 80%, therefore offers the possibility of synthesizing the active principles of formula I b and their analogs, in a new and original way.

According to the invention, the oxazolin-2-yl-1, 1 ′ -biphenyl derivatives of formula I are prepared by carrying out the following steps: a) the biphenyl-2-carboxylic acid of formula:

in an appropriate medium, such as an aprotic solvent, for example methylene chloride, first with oxalyl chloride, then with 2-amino-2- methylpropanol or DL-2-amino-1-propanol and finally with thionyl chloride, to give a derivative of 2- (1, 3-oxazolin-2-yl) -1, 1 '-biphenyl of general formula:

in which R has the same meaning as previously b) reacting the derivative 1, 1 '-biphenyl thus obtained with phthalimide in the presence of formaldehyde polymerized or not such as paraformaldehyde or trioxane, and in the presence of a strong acid as catalyst, to form the desired compound of formula I. This last reaction can be carried out directly in the strong acid in question, in general a sulfonic acid such as methanesulfonic acid which then plays the additional role of solvent, or alternatively in an organic solvent containing this strong acid.

In this case, an aliphatic carboxylic acid such as acetic or propionic acid or a nitroaliphatic or nitroaryl derivative such as nitromethane or nitrobenzene is generally preferred as suitable organic solvent, the strong acid generally being a sulfonic acid such as as above, or a mineral oxacid such as sulfuric acid. This is usually used at a rate of 1 to 3 equivalents by volume relative to the solvent, preferably 3 equivalents.

The reaction in question takes place in most cases at room temperature or by heating to a temperature not exceeding 60 ° C. while the phthalimide is used in an amount of 1 to 2 molar equivalents relative to the compound of formula III . As for the biphenyl-2'-carboxylic acid of formula II, it can be obtained according to known methods for example by heating the fluorenone of formula:

in the presence of an alkaline base such as an alkali metal hydroxide, preferably sodium or potassium hydroxide, then treatment of the salt obtained with a strong acid to finally obtain the desired acid of formula II.

As indicated above, the derivatives of 2- (1, 3-oxazolin-2-yl) -4'- phthalimidomethyl-1, 1 '-biphenyl of formula I can be used for the preparation of 4'-aminomethyl-2-cyano -1, 1 '-biphenyl of formula la.

Consequently, the invention relates to the compounds of formula I as intermediates for the final synthesis of the compound of formula la, in particular the compound of formula I in which R represents the methyl radical. For example, this compound of formula la can be prepared, starting from compounds of formula I, by implementing a process comprising the following series of steps: a) the compound of formula I is treated with oxychloride of phosphorus in a polar solvent such as pyridine, which provides 4'-phthalimidomethyl-2-cyano-1, 1 '-biphenyl of formula:

This reaction usually takes place at a temperature of the order of 80 ° C. to 90 ° C. in the presence of an excess of phosphorus oxychioride, that is to say up to 2 molar equivalents per molar equivalent of compound of formula I, thereby providing the desired compound with yields of about 90%. b) the phthalimido derivative of formula V is then reacted with ethylenediamine or a buffered hydrazine / acetic acid solution, to obtain the desired 4'-aminomethyl-2-cyano-1, 1 '-biphenyl.

The reaction in question is carried out in the presence of an excess of reagents of up to 2 molar equivalents of ethylenediamine or 2 molar equivalents of hydrazine buffered by a molar equivalent of acetic acid, relative to the compound of formula V , which makes it possible to obtain the desired compound according to yields varying from 60 to 85%.

As indicated above, the compounds of formula I can be used for the synthesis of the compound of formula itself which is intermediate for the preparation of the biphenyl derivatives of formula Ib.

Consequently, the invention also relates to the compounds of formula I as intermediates for the final synthesis of the biphenyl derivatives of formula Ib, in particular for the synthesis of irbesartan.

For example, these compounds of formula Ib can be prepared from the carbonitrile derivative of formula la obtained itself according to the invention from compounds of formula I, by implementing a process comprising the following steps -after:

(A) the carbonitrile derivative of formula la is condensed with a compound of general formula: H - Am VI in which Am has the same meaning as above, in the presence of a catalyst suitable for obtaining the cyano-biphenyl derivatives of general formula :

in which Am has the same meaning as before. This reaction takes place, in general, by heating the reagents, in the presence at a temperature above 100 ° C, for example from 100 ° C to 130 ° C in an appropriate solvent which is usually an aprotic solvent such as a particular ether. dibutyl ether or in an aromatic compound such as a halobenzene for example chlorobenzene or an aromatic hydrocarbon such as toluene or a xylene.

The coupling of the aminonitrile compound of formula la with the compound of formula VI is carried out in the presence of a catalyst containing a transition metal more particularly a metal from the group of lanthanides or rare earths, namely ytterbium or praseodyme.

Among the catalysts which have proved effective, there may be mentioned ytterbium salts and praseodymium salts, for example praseodymium acetate (III +) but more particularly and, preferably, ytterbium trifluoromethanesulfonate (III +) and praseodymium trifluoromethanesulfonate (III +).

In this way, the compounds of formula VII can be obtained in particularly advantageous yields. For example, the aminonitrile of formula la coupled to 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one in the presence of praseodymium trifluoromethanesulfonate (III +) or ytterbium (III +) provides the corresponding compound of formula VII with yields of the order of 65%. (b) the nitrile group of the compound of formula is then transformed

VII into a tetrazolyl group optionally protected, for example by means of a trityl group, by treatment of the compound of formula VII by means of an azide derivative, for example tributyltin azide or sodium azide and deprotection, if necessary, by acid hydrolysis to finally give the desired compounds of formula Ib.

The following nonlimiting examples illustrate the invention. These examples refer to infrared spectra (IR) and nuclear magnetic resonance (NMR) spectra in which the abbreviations "s" and "m" have the meanings of "singlet" and "multiplet" respectively.

PREPARATIONS

a) 2- (4.4-Dimethyl-1, 3-oxazolin-2-yl) -1.1 '-biphenyle To a solution of 11.9g (60 mmol) 2-biphenyl-carboxylic acid in 60ml of dry methylene chloride , cooled to 0 ° C., 6.2 ml (72 mmol) of oxalyl chloride are added dropwise. The mixture is kept under stirring for 12 hours at room temperature and then at 35 ° C for 4 hours. The solvent and the excess oxalyl chloride are removed in vacuo and the residue is dissolved in 50 ml of methylene chloride. This solution is then added dropwise to a cooled solution of 10.7 g (0.12 mole) of 2-amino-2-methylpropanol in 50 ml of methylene chloride. The mixture is stirred for 10 to 12 hours at room temperature, filtered and evaporated in vacuo.

The oily residue is diluted in 10 ml of methylene chloride and treated, with stirring, with 6.6 ml (90 mmol) of thionyl chloride. After 30 minutes, 100 ml of water are carefully added, then the aqueous phase is separated, neutralized to a pH of about 7 by adding a 20% aqueous sodium hydroxide solution and extracted with 3 times 100 ml of water. 'diethyl ether. The organic fractions are combined, washed with water and then dried over anhydrous sodium sulfate. By evaporation of the solvent under vacuum, 14.4 g (yield: 96%) of desired product are obtained in the form of a yellowish oil of satisfactory purity (98% by high pressure liquid chromatography).

If necessary, further purify by distillation (e.g. 135-140 ° C / 0.6mm Hg) which provides 13.8g of 2- (4,4-dimethyl-1, 3-oxazolin-2-yl) - 1 , 1 '-biphenyle. Yield: 92%

Using the same precedent as described above, but replacing 2-amino-2-methylpropanol with DL-2-amino-1-propanol, we obtained 2- (4-methyl-1, 3-oxazolin -2-yl) -1, 1 '-biphenyl after purification by chromatography on silica (eluent: heptane / ethyl acetate 4/1) and distillation (145-150 ° C / 0.6mm Hg).

Yield: 46%

EXAMPLE I

2- (4,4-Dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1 '-biphenyl

To a cooled solution of 0.754 g (3 mmol) of 2- (4,4-dimethyl-1, 3-oxazolin-2-yl) -1, 1 '-biphenyl and 0.486 g (3.3 mmol) of phthalimide in 4.2 ml of nitromethane, 0.099 g (1.1 mmol) of trioxane is added and, drop by drop, 1.8 ml of 96% sulfuric acid. The mixture is stirred for 20 hours at room temperature, diluted with 20 ml of ethyl acetate and poured into a saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous phase is extracted with 2 times 30 ml of ethyl acetate. The extracts are combined, dried over anhydrous sodium sulfate and evaporated in vacuo.

In this way, 1.25 g of 2- (4,4-dimethyl-1,3-oxazolin-2-yl) - 4'-phthalimidomethyl-1,1 '-biphenyl are obtained in the form of a white powder which l '' is purified on a silica column (eluent: hexane / ethyl acetate)

Yield: 0.98 g or 80% m.p .: 115-119 ° C (methanol)

IR (KBr): 2964, 2927, 1716, 1654, 1393, 1349 cm ^"1 .

¹ H NMR (CDCI ₃ , 200MHz), δ, ppm: 1.27 (s, 6H); 3.79 (s, 2H); 4.89 (s, 2H);

7.29-7.51 (m, 7H); 7.66-7.78 (m, 3H); 7.81 -7.91 (m, 2H).

¹³ C NMR (CDCI ₃ , 50MHz), ppm: 168.0; 163.6; 141.0; 140.6; 135.2; 133.9; 132.0; 130.4; 130.1; 130.0; 128.6; 128.2; 127.8; 127.1; 123.3; 79.4; 67.4;

41, 3; 27.9. EXAMPLE II to V

2- (4,4-Dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1 '-biphenyl

To a cooled solution of 0.754 g (3 mmol) of 2- (4,4-dimethyl-1,3-oxazolin-2-yl) - 1,1 '-biphenyl and 0.486 g (3.3 mmol) of phthalimide 0.099 g (1.1 mmol) of trioxane and, dropwise, the strong acid are added to the solvent.

The mixture is kept stirring for H hours at temperature T, it is diluted in 20 ml of ethyl acetate and it is poured into a saturated aqueous sodium bicarbonate solution. The organic layer is separated and the aqueous phase is extracted with 2 times 30 ml of ethyl acetate. The extracts are combined, dried over anhydrous sodium sulfate and evaporated in vacuo.

In this way, the 2- (4,4-dimethyl-1,3-oxazolin-2yl) -4'- phthalimidomethyl-1,1-biphenyl is collected and purified on a silica column (eluent: h exa ne / ethyl acetate).

The following results were obtained:

EXAMPLE VI

2- (4-Methyl-1.3-oxazolin-2-vπ-4'-phthalimidomethyl-1, 1 '-biphenyl To a cooled solution of 0.237g (1 mmol) of 2- (4-methyl-1, 3-oxazolin -2-yl) -1, 1 '-biphenyl and 0.221 g (1.5 mmol) of phthalimide in 1.5 ml of nitromethane, 0.045g (1.5 mmol) of paraformaldehyde is added and, drop by drop, 0 , 5ml of 96% sulfuric acid.

The reaction mixture is kept at room temperature for 5 hours and the process is continued as described in Example I.

The desired compound is then purified on a silica column (eluent: hexane / ethyl acetate) to obtain 0.287 g (yield: 72%) of 2- (4-methyl-1, 3-oxazolin-2-yl) -4 '-phthalimidomethyl-1, 1' -biphenyl which is recrystallized from methanol. M.p .: 125-127 ° C

IR (KBr): 3027, 2965, 2891, 1770, 1715, 1652, 1428, 1393, 1348 cm ^"1. ¹ H NMR (CDCI ₃ , 200MHz), ppm, ppm: 1, 18-1, 30 (m, 6H); 3.56-3.72 (m, 1H); 4.10-4.33 (m, 2H); 4.89 (s, 2H); 7.29-7.52 (m, 7H ); 7.66-7.77 (m, 3H); 7.81 - 7.90 (m, 2H). ¹³ C NMR (CDCI ₃ , 50 MHz), ppm: 168.1; 164.9; 141 , .2; 140.8; 135.3;

134.1; 132.2; 130.6; 130.3; 130.2; 128.7; 128.3; 127.7; 127.2; 123.4; 74.4; 62.0; 41, 4; 21, 2.

EXAMPLE VII

4 '- (2-n-Butyl-4-spirocvclopentane-2-imidazolin-5-on-1-yl) methyl-2-cyano- 1, 1' -biphenyl

a) 4'-Phthalimidomethyl-2-cvano-1, 1 '-biphenyle To a solution of 11.28 g (27.5 mmol) of 2- (4,4-dimethyl-1,3-oxazolin-

2-yl) -4'-phthalimidomethyl-1, 1 '-biphenyl in 30 ml of anhydrous pyridine, 5.1 ml (56 mmol) of phosphorus oxychloride are added under cooling and dropwise. While stirring, the mixture is then heated to 85- 90 ° C for 3 hours. After cooling, the dark solution thus obtained is poured into ice water and extracted with 3 times 200 ml of methylene chloride.

The organic layers are combined, washed with water, with a 5% aqueous solution of hydrochloric acid, again with water and then twice with a saturated aqueous solution of sodium bicarbonate. It is dried over anhydrous sodium sulfate and the solution is filtered over neutral alumina.

The filtrate is evaporated in vacuo which gives 8.4 g of the desired product.

(Yield: 90%) In this way, 7.6 g of pure 4'-phthalimidomethyl-2-cyano-1, 1'-biphenyl are obtained after recrystallization from acetic acid. An analytical sample can be obtained by recrystallization from methanol.

Mp: 178-179 ° C b) 4'-Aminomethyl-2-cyano-1, 1 '-biphenyle Heated at reflux for 6 hours, 6.76 g (20 mmol) of 4'- phthalimidomethyl-2-cyano-1 , 1 '-biphenyle, 2ml (40 mmol) of hydrazine monohydrate and 1, 2ml of acetic acid dissolved in a mixture of 100ml of tetrahydrofuran and 100ml of isopropanol. The cooled suspension is filtered, the precipitate is washed with 50 ml of methanol and the filtrate is treated with 100 ml of a 5% sodium hydroxide solution. After 15 minutes, 200 ml of an aqueous sodium chloride solution are added and the mixture is extracted with 3 times 100 ml of a 3/1 mixture of diethyl ether / tetrahydrofuran.

The extracts are combined, washed with 2 times 100 ml of an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvents are evaporated in vacuo and distilled, which gives 3.39 g of 4'-aminomethyl-2-cyano-1 '1-biphenyl (yield: 82%) in the form of a viscous oil which solidifies slowly on standing. M.p .: 110-118 ° C c) 4 '- (2-n-Butyl-4-spirocyclopentane-2-imidazoline-5-on-1-yl) methyl- 2-cvano- 1, 1' -biphenyle

To a solution of 1.04 g (5 mmol) of 4'-aminomethyl-2-cyano-1,1 '- biphenyl in 15 ml of dibutyl ether, 0.971 g (5 mmol) of 2-n-butyl-4 is added -spirocyclopentane-2-imidazoline-5-one then 0.3g (about 0.48 mmol) ytterbium (III +) trifluoromethanesulfonate hydrate. The mixture is then stirred under argon for 22 hours at 110-115 ° C and then, after cooling, the solution is washed first with water and then with an aqueous solution of sodium chloride. Dried over anhydrous sodium sulfate and evaporated in vacuo.

The residue is chromatographed on a silica column (eluent: heptane / ethyl acetate 2/1) which gives 1.25 g of 4 '- (2-n-butyl-4-spirocyclopentane-2-imidazoline-5-on- 1-yl) methyl-2-cyano-1, 1 '-biphenyl.

Yield: 65% EXAMPLE VIII

2-n-Butyl-4-spirocvclopentane-1-r (2 '- (tetrazol-5-yl) -4-biphenylyl) methyl] - 2-imidazolin-5-one or irbesartan

a) 2-n-Butyl-4-spirocyclopentane-1-r (2 '- (triphenylmethyl-tetrazol-5-yl) -

4-biphenylyl) methyl] -2-imidazolin-5-one

Is heated at reflux for 66 hours, 1.56 g of 4 '- (2-n-butyl-4-spirocyclopentane-2-imidazoline-5-on-1-yl) methyl-2-cyano-1, 1' -biphenyl , 2.6 g of tributyltin azide and 30 ml of xylene. The xylene is evaporated and the residue is dissolved in 20 ml of dichloromethane and 5 ml of tetrahydrofuran by adding 0.8 ml of a 10N sodium hydroxide solution. After 30 minutes of stirring, 2.5 g of trityl chloride are introduced and the mixture is left stirring for 26 hours. After evaporation of the solvents, the residue is taken up in ethyl acetate and washed with water, with a 3% potassium acid sulfate solution and with water. We dry and evaporate. The residue is then chromatographed on alumina, eluting with a hexane / ethyl acetate mixture (9/1 v / v).

In this way, 1.97 g of the desired compound are obtained. M.p .: 150-152 ° C b) irbesartan

1.96 g of the compound obtained in step a) above are dissolved in 10 ml of methanol and 10 ml of tetrahydrofuran. After the reaction medium has cooled to 5 ° C., 1.5 ml of 4N hydrochloric acid are added and the mixture is stirred for 3 hours at room temperature and 1 hour at 30 ° C. After evaporation of the solvents, the residue is taken up in water and brought to pH = 12 by addition of 10N sodium hydroxide.

The aqueous phase is extracted with diethyl ether, toluene and again with diethyl ether.

The aqueous phase is acidified to pH = 2 by addition of 1N hydrochloric acid, then extracted with ethyl acetate, dried and evaporated.

The white solid obtained is then dried at 50 ° C under 0.05mm Hg.

In this way, 0.840 g of irbesartan is collected. M.p .: 180-181 ° C

Claims

1. Derivatives of 1, 3-oxazolin-2-yl-1, 1 'biphenyle of general formula:

in which R represents hydrogen or the methyl radical.

2. 2- (4,4-Dimethyl-1, 3-oxazolin-2yl) -4'-phthalimidomethyl-1, 1 '- biphenyl.

3. 2- (4-Methyl-1, 3-oxazolin-2-yl) -4'-phthalimidomethyl-1, 1 '-biphenyl.

4. Process for the preparation of 1, 3-oxazolin-2-yl-1, 1'-biphenyl derivatives according to one of Claims 1 to 3, characterized in that: a) biphenyl-2- acid is treated carboxylic of formula:

in an appropriate medium first with oxalyl chloride, then with 2-amino-2-methylpropanol or DL-2-amino-1-propanoi and finally with thionyl chloride to give a derivative of (1, 3-oxazolin-2-yl) -1, 1 '-biphenyl of general formula:

in which R represents hydrogen or the methyl radical b) the 1,1 '-biphenyl derivative thus obtained is reacted with the phthalimide in the presence of formaldehyde, polymerized or not, in a strong acid as solvent and catalyst or in a organic solvent in the presence of a strong acid as catalyst, which provides the desired compounds.

5. Method according to Claim 4, characterized in that the polymerized formaldehyde is paraformaldehyde or trioxane.

6. Method according to Claim 4 or 5, characterized in that the reaction is carried out in a strong acid which is a sulfonic acid.

7. Method according to Claim 4 or 5, characterized in that the reaction is carried out in an organic solvent which is an aliphatic carboxylic acid or a nitroaliphatic or nitroaryl derivative, and in the presence of a strong acid which is a sulfonic acid or a mineral oxacid.

8. Method according to one of Claims 4 to 7, characterized in that the sulfonic acid is methanesulfonic acid.

9. Method according to Claim 7, characterized in that the aliphatic carboxylic acid is acetic or propionic acid.

10. Method according to Claim 7, characterized in that the nitroaliphatic derivative is nitromethane and the nitroaryl derivative is nitrobenzene.

11. Method according to Claim 7, characterized in that the mineral oxacid is sulfuric acid.

12. Process for the preparation of 4'-aminomethyl-2-cyano-1, 1 '-biphenyl of formula:

characterized in that: a) a compound of general formula is treated

in which R represents hydrogen or the methyl radical, with phosphorus oxychloride in a polar solvent, which provides 4'-phthalimidomethyl-2-cyano-1, 1 '-biphenyl of formula:

b) the phthalimido derivative thus formed is then reacted with ethylenediamine or a buffered hydrazine / acetic acid solution to obtain the desired deprotected amine.

13. Process for the preparation of biphenyl derivatives of general formula:

in which Am represents a spirocyclopentane-keto-imidazolinyl, 1 H-imidazolyl or 1 H-benzimidazolyl group, this group itself comprising one or more substituents selected from halogen atoms, CC ₄ alkyl groups, C1 aikoxy -C4 and carboxylic, characterized in that: a) a compound of general formula is treated:

in which R represents hydrogen or the methyl radical, with phosphorus oxychloride in a polar solvent, which gives 4'-phthalimidomethyl-2-cyano- 1, 1 '-biphenyl of formula

b) the phthalimido derivative thus formed is then reacted with ethylenediamine or a buffered hydrazine / acetic acid solution, to obtain the 4'-aminomethyl-2-cyano-1, 1 '-biphenyl of formula:

c) condensing the carbonitrile derivative thus formed, with a compound of general formula:

H - Am in which Am has the same meaning as above, in the presence of a catalyst containing a metal from the lanthanide group, to obtain the cyanobiphenyl derivatives of general formula:

in which Am has the same meaning as before, d) the cyano group of the cyanobiphenyl derivative thus formed is finally transformed into an optionally protected tetrazolyl group by treatment of the compound of formula VII with an azide derivative and deprotection, if necessary, by acid hydrolysis, to obtain the desired compound.

14. Method according to Claim 13, characterized in that the metal of the lanthanide group is ytterbium or praseodyme.

15. Method according to Claim 13 or 14, characterized in that the catalyst is a ytterbium or praseodyme salt.

16. Method according to Claim 15, characterized in that the catalyst is ytterbium (III +) trifluoromethanesulfonate or praseodyme (III +) trifluoromethanesulfonate.

17. Method according to Claim 13, characterized in that the tetrazolyl group is protected by a trityl group.

18. Method according to Claim 13, characterized in that the azide derivative is tributyltin azide or sodium azide.

19. Method according to one of Claims 13 to 18, characterized in that Am represents the group 2-n-butyl-4-spirocyclopentane-5-keto-2-imidazolin-1-yl.